Table 1.
Metabolomic studies focusing on the diagnosis of sepsis.
| Study (Year) | Sample Type | Participants (Septic:Comparator) |
Age Group | Comparator | Analytical Technique | Statistical Analysis Methods | Raised in Sepsis | Reduced in Sepsis |
|---|---|---|---|---|---|---|---|---|
| Li et al. [42] (2021) | Serum | 84:59 | Paediatric | Healthy control | HPLC-MS (targeted) |
ANOVA, t-test, PCA, OPLS-DA, HCA, LR | D-mannose, d-quinovose, glycocholic acid, L-glutamate | PC (O-17:1/0:0), PI (20:4/18:1), PG (23:0/20:4), PE(P-17:0/0:0) |
| Mierzchala-Pasierb et al. [37] (2021) | Serum and urine | 15:15 | Adults | Healthy control | LC-MS (targeted) |
MW-U test, t-test, Cox’s PHR, Spearman’s correlation, ROC analysis | Arginine, glycine, thioproline—in both. Histidine, a-aminoisobutyric acid, sarcosine aminoadipic acid, tyrosine, phenylalanine, leucine, lysine, isoleucine, ornithine, threonine, 4-hydroxyproline, glutamine 3-methyl-histidine, asparagine, aminopimelic acid—in serum. Citrulline—in urine |
Histidine, aminoadipic acid, 3-methyl-histidine and aminopimelic acid—in urine. Dipeptide Gly-Pro—in serum |
| Jaurila et al. [27] (2020) | Serum | 44:14 | Adults | Healthy control |
1H-NMR (targeted) |
MW-U or t-test, FET, correlations | Glucose, glycine, creatinine, 3-hydroxybutyrate, glycoprotein acetyls mostly AGP | Citrate and histidine |
| Lin et al. [21] (2020) | Serum | 31:23 | Adults | Healthy control | GC–MS (targeted) |
PLS-DA, t-test, ROC analysis, correlation analysis | Six FAs (including tetradecanoic acid [12-methyl-, methyl ester, (S)-], hexanoic acid, 2-methyloctadecanoic acid, palmitoleic acid, myristoleic acid, and 3-hydroxyoctanoic acid), amino acids (including leucine, glutamic acid, cysteine, methionine, phenylalanine, putrescine, and aspartic acid), six amino acid derivatives, twenty-seven organic acids (including lactic acid, adipic acid, and 3-hydroxypropionic acid), pyruvic acid and (NADP)-NADPH, two TCA cycle derivatives (including DL-gamma-methyl-ketoglutaramate isomer and dimethyl fumarate), seven TCA cycle metabolites | Two BCFAs (3-methyl-2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid), ten saturated FAs (DPA, hexanoic acid, arachidic acid, palmitic acid, margaric acid, 10,13-dimethyltetradecanoic acid, nonadecanoic acid, pentadecanoic acid, propanedioic acid, methyl, ethyl ester, and stearic acid), nine unsaturated FAs (11,14-EDA, 11,14,17-ETA, adrenic acid, arachidonic acid, conjugated linoleic acid, bishomo-gamma-linolenic acid, linoleic acid, DHA, EPA), tryptophan, glutamine, serine, d-Proline, (N-methoxycarbonyl-, octyl ester), asparagine, 2 amino acid derivatives, citraconic acid, citramalic acid, DL-gamma-methylketoglutaramate isomer 1 and four TCA cycle metabolites |
| Sharma et al. [43] (2019) | Plasma | 27:23 | Adults | Healthy control | LC–MS/MS (targeted), ELISA tests | ANOVA, KWT | - | Total cholesterol, HDCH, LDCH, non-HDCH, Apo-A1, Apo-B100 andparaoxonase 1. |
| Sharma et al. [44] (2017) | Plasma | 33:23 | Adults | Healthy control | LC–MS/MS (targeted) and enzymatic colorimetry | Tukey’s HSD test, ANOVA | - | Total cholesterol, HDCH, LDCH, HDFC |
| Mecatti et al. [45] (2018) | Plasma and erythrocytes |
20:20 (Sepsis and septic shock: healthy control) |
Adults | Healthy control | LC-MS and GC-MS (targeted) |
PCA, OPLS-DA | PCs (C15:0/18:2, C16:0/18:1) only in plasma. Total MUFAs, oleic acid (C18:1 n-9), PS (C18:0/22:1), PC (C16:0/20:4) only in erythrocytes. CL (1′ [18:0/18:2]/3′ [20:0/20:0]) and PC (C16:0/18:2 and C16:0/20:5) in both. |
LPC (18:2/0:0), SM (d18:1/16:0), DHA (C22:6 n-3), PC (16:0/20:3) only in plasma. Total n-3 PUFAs, DPA (C22:5 n-3), PC (C15:0/18:2, C16:0/20:1) only in erythrocytes. Nine SMs (d18:1/20:1, d18:1/22:1 (d18:2/22:0), (d18:1/22:0)/(d16:1/24:0), (d18:0/22:0)/(d16:0/24:0), (d18:2/23:0), (d18:1/23:0), (d18:2/24:0)/(d18:1/24:1), (d18:1/24:0)/(d18:0/24:1), d18:1/17:0), 8 LPCs (15:0/0:0, 16:0/0:0, 18:3/0:0, 18:1/0:0, 18:0/0:0, 20:5/0:0, 20:4/0:0, 20:3/0:0), and PC (16:0/20:1) in both. |
| Szelig et al. [36] (2016) |
Serum and urine | 20:25 (Septic shock or severe sepsis:healthy control) |
Adults | Healthy control | HPLC (targeted) |
MW-U or t-test, Kruskal–Wallis and Spearman’s rho test | Serum meta-tyrosine on days 2 and 3. Urinary ortho-tyrosine on days 1 to 5, and urinary para-tyrosine on days 4 and 5. | Serum para-tyrosine on days 1 and 2. Urinary para-tyrosine on day 1. |
| Liang et al. [19] (2015) |
Urine | 1282:1346 (Septic shock: healthy control) |
Adults | Healthy control | UPLC-MS (untargeted) | OPLS-DA, ROC analysis | Hippuric acid, 3-methyluridine, acetylcysteine | Kynurenic acid, glycine |
| Su et al. [38] (2015) | Serum | 35:18 | Adults | Healthy control | LC-MS/MS (targeted) | ANOVA, Χ2 and t-test, ROC curves, Pearson correlation. | Arginine, aspartic acid, homocitrulline, ethanolamine, glutamine, glutamic acid, phenylalanine, taurine, SAAs—on ICU admission | Cystathionine, EAAs, anserine BCAAs, BCAA/AAA ratio, asparagine, carnosine, citrulline, histidine, Isoleucine, isoleucine, valine, lysine, ornithine, phosphoethanolamine, proline, sarcosine, threonine, tryptophan, tyrosine—on ICU admission |
| Fanos et al. [22] (2014) |
Urine | 9:16 | Neonates | Healthy control |
1H-NMR and GC-MS (untargeted) |
OPLS-DA | Lactate, glucose and maltose | 2,3,4-trihydroxybutyric acid, rabitol 3,4-dihydroxybutanoic acid, ribonic acid, 3,4,5-trihydroxypentanoic acid, 2-ketogluconic acid, pseudouridine. |
| Mickiewicz et al. [23] (2013) |
Serum | 21:13—Infants 20:18—Toddlers 14:9—School Age |
Infants, Toddlers, School Age |
Healthy control | 1H-NMR (targeted and untargeted) | PCA, PLS-DA, OPLS-DA, ROC analysis | 2-Hydroxybutyrate, 2-hydroxyisovalerate, lactate in all three. Creatinine and 2-oxoisocaproate in infants and school age. Phenylalanine in school age and toddlers. 3-hydroxybutyrate, acetone, betaine, glucose and isobutyrate in toddlers. Arginine, carnitine, creatine, creatine phosphate, histidine, myo-inositol, O-acetylcarnitine in school age. | 2-Aminobutyrate in infants and toddlers; acetate, adipate, threonine in infants. Glutamine in toddlers and citrate in school age. |
| Stringer et al. [46] (2011) | Plasma | 13:6 | Adults | Healthy control |
1H-NMR (targeted) |
Spearman’s correlation, t-test | Adenosine, Total Glutathione, PS | Sphingomyelin |
| Gaddnas et al. [47] (2009) | Serum | 44:15 (Severe sepsis:healthy controls) | Adults | Healthy control |
Radioimmunological assays | Χ2-test or FET, MW-U test, ROC analysis | Procollagen type III aminoterminal propeptides and crosslinked telopeptides of type I collagen. | - |
| Drobnik et al. [48] (2003) | Plasma | 102:56 | Adults | Healthy control |
LC-MS/MS (targeted) | MW-U test, ROC analysis | Ceramides (C16:0, C18:0, C20:0, C22:1, C24:1 and total form), LPC (16:0, 18:0, 18:1, 18:2 and total form), LPC-PC ratio (16:0, 18:0, 18:1,18:2 and total form) | Ceramides (C23:0, C24:0) |
| Reisinger et al. [39] (2021) |
Serum | 52:25 | Adults | ICU controls (without sepsis or bacteremia) |
1H-NMR (untargeted) and Bruker IVDr lipoprotein analysis |
LR, LMM, FET, Χ2 or MW-U test, PCA, PLS and OPLS-DA, correlations | VLPN, TG, V4 and V5TG, V2-V4FC, V4PL, L1TG, VLAB and ABA1 | Valine, leucine, isoleucine, HDFC, H1-H3FC, HDCH, H1-H3CH, HDPL, H2-H4PL, TPA1, HDA1 and H1-H4A1 |
| Grauslys et al. [24] (2020) |
Serum | 55:58 | Paediatrics | SIRS |
1H-NMR (targeted) |
PCA, PLS-DA, t-test | 3-hydroxtbutyrate, lactate, urea, valine, phenylalanine | 2-hydroxyisobutyrate, acetate, acetone, leucine, pyruvate. |
| Antcliffe et al. [40] (2017) |
Serum | 15:26 (Pneumonia:brain injury) | Adults | SIRS (brain injury) |
1H-NMR (targeted and untargeted) |
PCA, OPLS-DA, CV-ANOVA, ROC analysis | Lipids, formate, phenylalanine, N and O-glycoproteins, unidentified metabolite (at 3.570–3.575 ppm). Lipoproteins (V5FC, L1-L4TG, L1PL, HDTG, H1and H2TG, L1 and L6AB). | Phospholipids (choline), glutamine and alanine. Lipoproteins (H3 and H4FC, L5 and L6FC, HDA1 and H4A1, TPA1 and TPA2, HDA2 and H4A2, HDCH, H3 and H4CH, L6CH, H4PL, L6PL). |
|
Neugebauer et al. [20] (2016) |
Serum | 322:84 (Total) 123:42 (Test) 59:24 (Confirmation) |
Adults | SIRS | LC-MS/MS (targeted) | MW-U test or t-test, HCA, LR, ROC analysis, KMSA | Serine, spermine, spermidine, aspartate, phenylalanine, total dimethylarginine, kynurenine, acetylornithine, acylcarnitine C6(C4:1-DC), PCaa (C32:0), SM (C16:1) | SM (C22:3, C20:2, C24:0, C26:1), SM-OH (C22:1, C24:1), LPCa (C24:0, C14:0), PCaa (C32:0, C32:2, C36:6, C40:4, C42:6), PCae (C44:4), acylcarnitine C16:2(OH) |
| Kauppi et al. [26] (2016) | Whole blood | 65:49 (Bacteremic sepsis:SIRS) |
Adults | SIRS | GC-TOF-MS (Untargeted) |
H-MCR, OPLS-DA | Myristic acid, pyruvic acid | Isoleucine, norleucine, citric acid and a phosphocholine-like derivative |
| Mickiewicz et al. [32] (2015) |
Serum and plasma | 37:20 (Septic shock: SIRS) |
Adults | SIRS |
1H-NMR (targeted), cytokine and chemokine assay kits |
PCA, OPLS-DA, ROC analysis | Proline, 3-hydroxybutyrate, isobutyrate, phenylalanine, myoinositol, 2-hyroxybutyrate, O-acetylcarnitine, urea, IP-10, HGF, IL-2Ra, IL-1Ra, IL-18 | Valine, arginine, threonine, glutamate, glucose, methanol, propylene glycol, TNF-β, IL-1α, MCP-3 |
| Su et al. [38] (2015) | Serum | 35:14 | Adults | SIRS | LC-MS/MS (targeted) | ANOVA, Χ2 test, t-test, Pearson correlation, ROC analysis | Homocitrulline, cystathionine, ethanolamine—at ICU admission | Anserine, phosphoethanolamine, lysine, δ-hydroxylysine, phosphoserine—at ICU admission |
| Mickiewicz et al. [25] (2014) |
Serum | 39:20 (Septic shock: SIRS) |
Adults | SIRS |
1H-NMR (targeted) |
PCA, OPLS-DA, ROC analysis | Sucrose, lactate, myoinositol, proline, O-acetylcarnitine, isobutyrate, succinate, urea, creatinine, creatine, 2-hydroxyisovalerate, trimethylamine-N-oxide, 3-hydroxybutyrate, phenylalanine | Isoleucine, leucine, valine, lysine, glycine, serine, glutamine, alanine, threonine, glucose, mannose, glutamate, arginine, 2-aminobutyrate, methanol, 2-oxobutyrate, creatine phosphate |
| Su et al. [34] (2014) | Serum | 35:15 | Adults | SIRS | LC-MS/MS (targeted) |
PCA, PLS and OPL-DA, MW-U test, ROC analysis | S-(3-methylbutanoyl)-dihydrolipoamide-E and N-nonanoyl glycine | Lactitol dehydrate and S-phenyl-D-cysteine |
| Mickiewicz et al. [23] (2013) | Serum | 21:13—Infants 20:16—Toddlers 14:9—School Age |
Infants, Toddlers, School Age |
SIRS |
1H-NMR (untargeted and targeted) |
PCA, PLS-DA, OPLS-DA, ROC analysis | 2-Hydroxybutyrate and glycerol in infants and school age. Glucose in infants and toddlers. Arginine in toddlers and school age. Citrate only in toddlers. Lactate, alanine, asparagine, creatine, creatine phosphate, creatinine 2-oxoisocaproate, ethanol, methanol, phenylalanine, taurine in school age. | Taurine in infants and toddlers. Adipate, alanine, glutamate, glycine, hopoxanthine, isoleucine, lactate, methionine, ornithine, serine, pyruvate, suberate, threonine in infants. |
|
Schmerler et al. [30] (2012) |
Plasma | 69:74 (Total) 30:33 (Training) 39:41 (Test) |
Adults | SIRS | LC-MS/MS (targeted) | MW-U or t-test, ROC analysis | Acylcarnitines (C3, C5, C6 (C4:1-DC), C8, C10:1). PCaa (C32:0, C34:1, C36:1), PCae (C34:1) | - |
| Su et al. [38] (2015) |
Serum | 12:23 | Adults | Severe sepsis |
LC-MS/MS (targeted) | ANOVA, Χ2 test, t-test, Pearson correlation, ROC analysis | Taurine (on days 1, 3, 5, 7, 10, and 14), cystine (on days 3, 7, 10, and 14), SAAs (on days 5, 10, and 14), whilst arginine, asparagine, aspartic acid, glutamic acid, leucine, serine, tryptophan, BCAAs, BCAA/AAA ratio—at certain time points | 3-methyl-L-histidine, α-aminoadipic acid, α-amino-n-butyric acid, argininosuccinic acid, β-amino-isobutyric acid, carnosine, cystathionine, glutamine, phenylalanine, proline—at certain timepoints |
| Su et al. [34] (2014) |
Serum | 10:25 | Adults | Severe sepsis |
LC-MS/MS (targeted) |
MW-U, PCA, PLS and OPL-DA, ROC analysis | Ne, Ne-dimethyllysine, glyceryl-phosphoryl-ethanolamine, 2-phenylacetamide, D-cysteine | - |
| Beloborodova et al. [28] (2019) |
Serum | 35:48 (Late: early-stage sepsis) | Adults | Early-stage sepsis | GC-MS | MW-U, Spearman’s correlation | Succinic acid, fumaric acid, p-HPhLA | - |
Studies with validation cohorts are highlighted in bold. Abbreviations, LC: liquid chromatography; HPLC: high-performance liquid chromatography; GC: gas chromatography; MS: mass spectrometry; TOF-MS: time-of-flight mass spectrometry; MS/MS: tandem mass spectrometry; 1H-NMR: 1H-nuclear magnetic resonance; LR: logistic regression; LMM: linear mixed model; HCA: hierarchical clustering analysis; PCA: principal Component analysis; PLS-DA: partial least squares discriminant analysis; OPLS-DA: orthogonal projections to latent structures discriminant analysis; ANOVA: analysis of variance; CV-ANOVA: cross-validated ANOVA; MW-U: Mann-Whitney U; H-MCR: hierarchical multivariate curve resolution; KMSA: Kaplan-Meier survival analysis; ROC: receiver operating characteristic; Χ2: chi-square; FET: Fisher’s exact test; KWT: Kruskal-Wallis test; DHA: docosahexaenoic acid; DPA: docosapentaenoic acid; EPA: eicosapentaenoic acid; EDA: eicosadienoic acid; ETA: eicosatrienoic acid; NADP: nicotinamide adenine dinucleotide phosphate; EAAs: essential amino acids; AAAs: aromatic amino acids; BCAAs: branched-chain amino acids; BCFAs: branched-chain fatty acids; SAAs: sulphur containing amino acids; AGP: alpha-1-acid glycoprotein; Cer: ceramide, SM: sphingomyelin; PC: phosphatidylcholine; LPC: lysophosphatidylcholine; GPC: glycerophosphocholine; PS: phosphatidylserine; PI: phosphatidylinositol; PE: phosphatidylethanolamine; CL: cardiolipin; aa: diacyl; ae: acyl-alkyl; PUFA: polyunsaturated fatty acid; MUFA: monounsaturated fatty acid; HGF: hepatocyte growth factor; IL: interleukin; IP-10: interferon-inducible protein-10; Ra: receptor antagonist; p-HPhLA: p-(hydroxyphenyl)lactic acid; TG: triglyceride; HDL: high-density lipoprotein; LDL: low-density lipoprotein; VLDL: very-low-density lipoprotein; Apo-A1: apolipoprotein A1; Apo-A2: apolipoprotein-AII; Apo-B100: apolipoprotein B100; ABA1: apo-B100 to apo-A1 ratio; HDCH: HDL cholesterol; HDFC: HDL-free cholesterol; LDCH: LDL cholesterol; VLPN: VLDL particle number; H1-H4FC: HDL-free cholesterol subfractions 1 to 4; L5 and L6FC: LDL-free cholesterol subtractions 5 and 6; V2-V4FC: VLDL-free cholesterol subfractions 2 to 4; HDA1: HDL ApoA1; H1-H4A1: HDL Apo-A1 subfractions 1 to 4; TPA1: total plasma Apo-A1; TPA2: total plasma Apo-A2, HDA2: HDL Apo-A2; VLAB: VLDL Apo-B100; H4A2: HDL Apo-A2 subfraction 4; H1-H4CH: HDL cholesterol subfractions 1 to 4; L6CH: LDL cholesterol subfraction 6; HDPL: HDL phospholipid; H2-H4PL: HDL phospholipid subfractions 2 to 4; L6PL: LDL phospholipid subfraction 6; V5FC: VLDL-free cholesterol subfraction 5; L1-L4TG: LDL triglyceride subfractions 1 to 4; HDTG: HDL triglyceride; V4PL: VLDL phospholipid subfraction 4; H1 and H2 TG: HDL triglyceride subfractions 1 and 2; V4 and V5TG: VLDL triglyceride subfractions 4 and 5; L1 and L6AB: LDL Apo-B100 subfractions 1 and 6; TCA: tricarboxylic acid; C in sphingomyelin backbone represents the number of carbon atoms in the fatty acid side chain, whilst d in sphingomyelin backbone denotes 2 hydroxyl groups; SIRS: systemic inflammatory response syndrome.